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Critical evaluation of molecular monitoring in malaria drug efficacy trials and pitfalls of length-polymorphic markers

Messerli, Camilla and Hofmann, Natalie E. and Beck, Hans-Peter and Felger, Ingrid. (2017) Critical evaluation of molecular monitoring in malaria drug efficacy trials and pitfalls of length-polymorphic markers. Antimicrobial agents and chemotherapy, 61 (1). e01500-16.

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Official URL: http://edoc.unibas.ch/54390/

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Abstract

Estimation of drug efficacy in antimalarial drug trials requires parasite genotyping to distinguish new infections from treatment failures. When using length-polymorphic molecular markers, preferential amplification of short fragments can compromise detection of coinfections, potentially leading to misclassification of treatment outcome. We quantified minority clone detectability and competition among msp1, msp2, and glurp amplicons using mixtures of Plasmodium falciparum strains and investigated the impact of template competition on genotyping outcomes in 44 paired field samples. Substantial amplification bias was detected for all three markers, with shorter fragments outperforming larger fragments. The strongest template competition was observed for the marker glurp Detection of glurp fragments in multiclonal infections was severely compromised. Eight of 44 sample pairs were identified as new infections by all three markers. Ten pairs were defined as new infections based on one marker alone, seven of which were defined by the questionable marker glurp The impact of size-dependent template competition on genotyping outcomes therefore calls for necessary amendments to the current WHO recommendations for PCR correction of malaria drug trial endpoints. Accuracy of genotyping outcomes could be improved by separate amplification reactions per allelic family and basing results on markers msp1 and msp2 first, with glurp only used to resolve discordant results.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Molecular Parasitology and Epidemiology (Beck)
UniBasel Contributors:Hofmann, Natalie and Beck, Hans-Peter and Felger, Ingrid
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:24 Apr 2017 12:35
Deposited On:24 Apr 2017 12:35

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